The PRISMA flow diagram can be found below.
The table of included studies is presented in Table 1.
| Name | Title | ID | Sponsor | Design | Population | Intervention | Sample size | Objectives | Start date | Completion date | Completion year | Status | Available data |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Fowler (2015) | A UGT2B10 Splicing Polymorphism Common in African Populations May Greatly Increase Drug Exposure | NA | Hoffmann-La Roche | DB-RCT; single ascending dose (phase I) | Men 18-45 years | RO5263397 (1mg to 125mg); Placebo | 49 | Tolerability, pharmacokinetics | NA | NA | 2015 | completed | None |
| JapicCTI-194581 (2019) | A Phase I Single-Ascending Dose and Multiple-Ascending Dose Study of RO6889450 in Healthy Japanese Male | JapicCTI-194581 | Hoffmann-La Roche | DB-RCT; single and multiple ascending dose (phase I) | Men 20-45 years | Ralmitaront; Placebo | 64 | Tolerability, pharmacokinetics | 27.01.19 | 23.10.19 | 2019 | completed | None |
| NCT02699372 (2016) | The Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of RO6889450 in Healthy Volunteers | BP30134, NCT02699372 | Hoffmann-La Roche | DB-RCT; single and multiple ascending dose up to 2 weeks (phase I) | Men/women 18-45 years | Ralmitaront (5 mg to 450mg); Placebo | 164 | Tolerability, pharmacokinetics | 21.03.16 | 14.04.17 | 2017 | completed | None |
| NCT04512066 (2020) | A Trial of the Efficacy and the Safety of RO6889450 (Ralmitaront) vs Placebo in Patients With an Acute Exacerbation of Schizophrenia or Schizoaffective Disorder | BP41743, NCT04512066, JPRN-jRCT2031200288 | Hoffmann-La Roche | DB-RCT; 8 weeks (up to 48 weeks extension) (phase II) | Men/women 18-45 years with schizophrenia or schizoaffective disorder (acute, DSM-5) | Ralmitaront 45mg/d; Ralmitaront 150mg/d; Risperidone 4mg/d; Placebo | 287 | Efficacy (acute), tolerability | 08.09.20 | 21.06.22 | 2022 | completed | Efficacy, dropouts, side-effects |
| NCT03669640 (2018) | A Study to Assess the Effects of RO6889450 (Ralmitaront) in Participants With Schizophrenia or Schizoaffective Disorder and Negative Symptoms | BP40283, NCT03669640, EUCTR2020-004752-16, JPRN-jRCT2031200287 | Hoffmann-La Roche | DB-RCT; 12 weeks (phase II) | Men/women 18-55 years with schizophrenia or schizoaffective (predominant negative symptoms, DSM-5) | Part A: Ralmitaront; placebo (monotherapy); Part B: Ralmitaront low or high dose; placebo (add-on to current antipsychotics) | 128 | Efficacy (negative symptoms), tolerability | 04.12.18 | 08.05.23 | 2023 | completed | None |
| DA801002 (in Galluppi 2021) | Population pharmacokinetic analysis of ulotaront in subjects with schizophrenia | DA801002 | Sunovion/Sumitomo | SB-RCT single ascending dose (phase I) | Men >18 years | Ulotaront (25mg to 50mg); Placebo | 16 | Pharmacokinetics | NA | NA | 2021 | completed | None |
| SEP361-101 (in Galluppi 2021 and Chen 2022) | A sensitive LC-MS/MS method for simultaneous quantification of ulotaront and its N-desmethyl metabolite in human plasma and application to a clinical study | SEP361-101 | Sunovion/Sumitomo | SB-RCT; single ascending dose (phase I) | Men >18 years | Ulotaront (5mg to 125mg); Placebo | 52 | Pharmacokinetics | NA | NA | 2021 | completed | None |
| Hopkins (2021) | Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans | SEP361-103 | Sunovion/Sumitomo | DB-RCT two-period crossover; single dose (phase I) | Men 18-35 years | Cohort 1: Ulotaront 10mg; Placebo; Cohort 2: Ulotaront 50mg; Placebo | 24 | Sleep parameters, pharmacokinetics | NA | NA | 2021 | completed | Dropouts, side-effects |
| Isaacson (2023) | Ulotaront, a Trace Amine-Associated Receptor 1/Serotonin 5-HT1A Agonist, in Patients With Parkinson Disease Psychosis: A Pilot Study. | SEP361-203, NCT02969369 | Sunovion/Sumitomo | DB-RCT; 6 weeks (with open label extension) (phase 2) | Men/women ≥55 years with Parkinson’s disease psychosis (acute) | Ulotaront 20-75mg/d; Placebo | 39 | Efficacy (acute), safety | 21.11.16 | 05.07.23 | 2023 | completed | Efficacy, dropouts, side-effects |
| NCT04072354 (2019) | A Clinical Trial to Study the Efficacy and Safety of an Investigational Drug in Acutely Psychotic People With Schizophrenia | SEP361-301, NCT04072354, EUCTR2019-000470-36 | Sunovion/Sumitomo | DB-RCT; 6 weeks (phase 3) | Men/women 13-17 and 18-65 years with schizophrenia (acute, DSM-5) | Ulotaront 50mg/d; Ulotaront 75mg/d; Placebo | 463 | Efficacy (acute), tolerability | 11.09.19 | 08.06.23 | 2023 | completed | Efficacy, dropouts |
| Koblan (2020) | A Non–D2-Receptor-Binding Drug for the Treatment of Schizophrenia | SEP361-201, NCT02969382, EUCTR2016-001555-41 | Sunovion/Sumitomo | DB-RCT; 4 weeks (with open label extension) (phase 2) | Men/women 18-40 years with schizophrenia (acute, DSM-5) | Ulotaront (50-75mg/d); Placebo | 245 | Efficacy (acute), tolerability | 05.12.16 | 31.07.18 | 2018 | completed | Efficacy, dropouts, side-effects |
| Perini (2023) | Effects of ulotaront on brain circuits of reward, working memory, and emotion processing in healthy volunteers with high or low schizotypy | SEP361-104, NCT01972711 | Sunovion/Sumitomo | DB-RCT; single dose (phase 1) | Men/women 18-45 years (high or low levels of schizotypy) | Ulotaront 50mg; Amisulpride 400mg; Placebo | 105 | fMRI | 41699 | 42186 | 2015 | completed | Dropouts, side-effects |
| NCT01940159 (2013) | A Study Assessing the Safety, Tolerability, and Pharmacokinetics of SEP-363856 in Male and Female Subjects With Schizophrenia | SEP361-105, NCT01940159 | Sunovion/Sumitomo | SB-RCT; single ascending dose (phase 1) | Men/women 18-50 years with schizophrenia (stable, DSM-IV-TR) | Ulotaront (50mg to 150mg); Placebo | 48 | Tolerability, pharmacokinetics | 41334 | 41730 | 2014 | completed | None |
| Szabo (2023) | A multicenter, double-blind, placebo-controlled, randomized, Phase 1b crossover trial comparing two doses of ulotaront with placebo in the treatment of narcolepsy-cataplexy. | SEP361-108 , NCT05015673 | Sunovion/Sumitomo | DB-RCT three-period crossover; 2 weeks (phase 1) | Men/women 18-55 years with narcolepsy/cataplexy | Ulotaront 25mg; Ulotaront 50mg; Placebo | 18 | Sleep parameters, pharmacokinetics, tolerability | 05.06.14 | 26.05.15 | 2015 | completed | Dropouts, side-effects |
| Koblan (2016) | A phase 1 open label safety and tolerability study of SEP-363856, a novel NON-D2 mechanism of action molecule, in patients with schizophrenia | SEP361-106, NCT01994473 | Sunovion/Sumitomo | SB-RCT; multiple ascending dose for 1 week (including open label extension) (phase 1) | Men/women 18-55 years with schizophrenia (stable, DSM-IV-TR) | Ulotaront (10mg/d to 100mg/d); Placebo | 48 | Tolerability, pharmacokinetics | 41334 | 41974 | 2014 | completed | None |
| NCT04092686 (2019) | A Clinical Trial That Will Study the Efficacy and Safety of an Investigational Drug in Acutely Psychotic People With Schizophrenia | SEP361-302, NCT04092686, EUCTR2019-000697-37 | Sunovion/Sumitomo | DB-RCT; 6 weeks (phase 3) | Men/women 18-65 years with schizophrenia (acute, DSM-5) | Ulotaront 75mg/d; Ulotaront 100mg/d; Placebo | 462 | Efficacy (acute), tolerability | 30.09.19 | 08.09.23 | 2023 | completed | Efficacy, dropouts |
| NCT04325737 (2020) | Study Assessing the Safety, Tolerability, and Pharmacokinetics of SEP-363856 in Japanese Male and Female Subjects With Schizophrenia | DA801102, NCT04325737, jRCT2080225100 | Sunovion/Sumitomo | DB-RCT; 2 weeks (phase 1) | Men/women 18-65 years with schizophrenia (stable, DSM-5) | Cohort 1: Ulotaront (50mg/d to 100mg/d); Placebo; Cohort 2: Ulotaront (25mg/d to 100mg/d); Placebo | 13 | Tolerability, pharmacokinetics | 31.03.20 | 07.08.20 | 2020 | completed | None |
| Tsukada (2023) | A randomized, single-dose, crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophrenia. | SEP361-114, NCT04369391 | Sunovion/Sumitomo | DB-RCT three-period crossover; single dose (phase 1) | Men/women 18-65 years with schizophrenia (stable, DSM-5) | Ulotaront 150mg; Placebo; Moxifloxacin 400mg (ineligible for the review) | 68 | QTc interval, tolerability, pharmacokinetics | 18.06.20 | 10.11.20 | 2020 | completed | Dropouts, side-effects |
| NCT04115319 (2019) | A Study of the Long-term Safety and Tolerability of an Investigational Drug in People With Schizophrenia. | SEP361-304, NCT04115319 , EUCTR2019-002259-40 | Sunovion/Sumitomo | DB-RCT; 52 weeks (phase 3) | Men/women 18-65 years with schizophrenia (stable, DSM-5) | Ulotaront 50-100mg/d; Quetiapine XR 400-800mg/d | 475 | Efficacy (maintenance), tolerability | 15.11.19 | 30.12.22 | 2022 | completed | None |
| NCT05729373 (2023) | A Clinical Study That Will Meaure How Well SEP-363856 Works and How Safe it is in Adults With Generalized Anixety Disorder | SEP361-226, NCT05729373, EUCTR2022-502077-42-00 | Sunovion/Sumitomo | DB-RCT; 8 weeks (phase 2/3) | Men/women 18-65 years with GAD (acute, DSM-5) | Ulotaront (50-75mg/d); Placebo | 464 | Efficacy (GAD), tolerability | 08.03.23 | 08.02.25 | NA | ongoing | None |
| NCT05593029 (2022) | A Trial of the Safety and Efficacy of SEP-363856 in the Treatment of Adults With Major Depressive Disorder | 382-201-00001, NCT05593029 | Sunovion/Sumitomo | DB-RCT; 14 weeks (phase 2/3) | Men/women 18-65 years with MDD (acute, DSM-5) | Ulotaront; Placebo (add-on to antidepressants) | 900 | Efficacy (MDD), tolerability | 09.11.22 | 45778 | NA | ongoing | None |
| NCT04825860 (2021) | A Clinical Trial to Evaluate the Efficacy and Safety of SEP-363856 in Acutely Psychotic People With Schizophrenia, Followed by an Open-label Extension Phase | DA801201, NCT04825860, jRCT2071210003 | Sunovion/Sumitomo | DB-RCT; 6 weeks (and open label extension) (phase 2/3) | Men/women 18-65 years with schizophrenia (acute, DSM-5) | Ulotaront 50mg/d; Ulotaront 75mg/d; Placebo | 480 | Efficacy (acute), tolerability | 29.03.21 | 30.06.25 | NA | ongoing | None |
| NCT05848700 (2023) | A Clinical Study to Learn if SEP-363856 Has Physical Dependence in Adults With Schizophrenia | SEP361-121, NCT05848700 | Sunovion/Sumitomo | DB-RCT; 10 weeks (phase 1) | Men/women 18-65 years with schizophrenia (stable, DSM-5) | Ulotaront continuation; Ulotaront discontinuation (switch to placebo) | 60 | Physical dependence, pharmacokinetics | 21.06.23 | 23.02.24 | NA | ongoing | None |
| NCT05542264 (2022) | A Clinical Study That Will Assess the Effect of SEP-363856 or Prior Antipsychotic (PA) Standard of Care on Body-weight Associated Parameters in Subjects With Schizophrenia | SEP361-122, NCT05542264 | Sunovion/Sumitomo | DB-RCT; 2 weeks (phase 1) | Men/women 18-65 years with schizophrenia (stable, DSM-5) | Ulotaront; Prior antipsychotics (risperidone, olanzapine, quetiapine, aripiprazole) | 60 | Metabolic parameters | 15.11.22 | 23.10.23 | NA | ongoing | None |
| NCT05402111 (2022) | A Clinical Study That Will Assess How Food Moves Through the Stomach and Effects Blood Glucose Levels in Subjects With Schizophrenia Taking SEP-363856 or and Prior Antipsychotic (PA) Standard | SEP361-124, NCT05402111 (2022) | Sunovion/Sumitomo | Open RCT two-period crossover; single dose (phase 1) | Men/women 18-65 years with schizophrenia (stable, DSM-5) | Ulotaront (25mg to 50mg); Prior antipsychotics (risperidone, olanzapine, quetiapine, aripiprazole) | 36 | Pharmacokinetics, metabolic parameters | 13.06.22 | 13.07.23 | NA | ongoing | None |
Table 1 Table of included studies.
Acute psychosis: There were five trials that provived data for the timepoint of 3-13 weeks: 1) One study on ralmitaront, i.e., NCT04512066 examining the comparisons of ralmitaront vs. placebo or risperidone in adults with schizophrenia or schizoaffective disorder. 2) Four studies on ulotaront, i.e., Isaacson 2023 in adults with Parkinson disease psychosis, and Koblan 2020, NCT04072354 and NCT04092686 in adults with schizophrenia. Unavailable trials: 1) The study NCT04072354 (ulotaront vs. placebo) consisted of adolescent and adult parts, but data for the former were not found and the status is unclear. 2) One study (NCT04825860) examining ulotaront vs. placebo in adults with schizophrenia is currently ongoing.
Clinically stable patients with psychosis: There were data from one trial that provided data for the timepoint 1 day - 2 weeks: Tsukada 2023 that was a single dose crossover trial examining mainly the effects of ulotaront vs. placebo or moxifloxacin (not relevant for this analysis) on QTc interval prolongation in stable patients with schizophrenia. Unavailable trials: 1) NCT04115319 examining the long-term efficacy and safety of ulotaront vs. quetiapine in clinically stable patients with schizophrenia (recently completed), 2) Seven trials examining single or multiple doses of ulotaront focusing on pharmacokinetics or safety (e.g., physical dependence or metabolic side-effects) (completed and unpublished: NCT01940159, Koblan 2016, NCT04325737, NCT04865835; ongoing NCT05848700, NCT05542264, NCT05402111). No study examining ralmitaront was found for clinically stable psychosis.
Other patient subgroups: No study with available data was found for other patient subgroup such as first-episode and predominant negative symptoms. Unavailable trials: One study examined ralmitaront vs. placebo (as monotherapy or add-on to current antipsychotic treatment) in patients with schizophrenia or schizoaffective disroder and predominant negative symptoms (NCT03669640), which was reported to be failed but no data were available to be synthesized.
Other mental health conditions: There was one crossover study examining ulotaront vs. placebo in patients with narcolepsy-cataplexy that provided safety data for the timepoint of 1 day - 2 weeks (Szabo 2023). Unavailable trials: Two trials are currently ongoing and examine the efficacy of ulotaront compared to placebo in patients with generalized anxiety disorder (NCT05729373) and major depression (NCT05593029). None of the trials examined ralmitaront in patients with other mental health conditions.
Healthy volunteers: There were four trials examining ulotaront in healthy volunteers that provided safety data for the timepoint of 1 day - 2 weeks: 1) One trial examining the effects of a single dose of ulotaront on fMRI compared to placebo or amisulpride in participants with low or high levels of schizotypy (Perini 2023; safety data were used, fMRI data deeemed not relevant for the first iteration of the review), 2) Two crossover trials examining the pharmacokinetics of single doses of ulotaront vs. placebo in healthy volunteers (SEP361-111 and SEP361-117 as reported in Chen 2023), and 3) One crossover trial examining the effects of single administration of two doses of ulotaront vs. placebo on sleep parameters in healthy volunteers (Hopkin 2021, only safety data were used in the first iteration, and data from the low dose were not used due to the crossover design of the study). Unavailable trials: 1) Three studies examining the pharmacokinetcis and safety of ralmitaront in healthy volunteers (Fowler 2015, JapicCTI-194581, NCT02699372), 2) Two studies examining the pharmacokinetics of ulotaront in healthy volunteers (SEP361-101 , DA801002).
Risk of bias was evaluated using the RoB2 tool for the primary outcome, i.e., overall symptoms. There were available data only for the primary timepoint (3 weeks - 13 weeks) in acutely ill patients with Parkinson disease psychosis (Isaacson 2023) and schizophrenia spectrum disorder (Koblan 2020, NCT04092686, NCT04072354, NCT04512066).
The risk of bias assessment per domain and study is reported in Figure 1.
Figure 1 Risk of bias for overall symptoms
Three of the studies had an overall high risk of bias due to high risk of bias in missing outcome data (either due to high dropout rates Issacson 2023 or due to the non-reporting of dropouts in the two unpublished studies NCT04072354 and NCT04092686). The other two studies (Koblan 2020 and NCT03669640) had some concerns overall due to some concerns in the domain of missing outcome data (high dropout rates with unclear impact on the findings).
No data available from RCT.
Meta-analysis of variance was not conducted because 1) SDs were not reported in two studies (NCT04072354 and NCT04092686) and thus they were imputed, 2) SD of change was reported in one of the studies on schizophrenia (Koblan 2020), while SD of endpoint scores in another studt (NCT04512066).
No data available from RCT.
No data available from RCT.
No data were available from the two unpublished acute studies on ulotaront (i.e., NCT04072354, NCT04092686).
No data available from RCT.
No data available from RCT.
No data were available from the two unpublished acute studies on ulotaront (i.e., NCT04072354, NCT04092686).
No data available from RCT.
No data available from RCT.
No data were available from the two unpublished acute studies on ulotaront (i.e., NCT04072354, NCT04092686).
No data available from RCT.
No data available from RCT.
Data were available only from the study on Parkinson disease psychosis (i.e., Isaachson 2023). No data from RCT on schizophrenia.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
Imputations of responders were required in the unpublished ulotaront studies (i.e., NCT04072354, NCT04092686); cutoff of 50% change from baseline was used.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
Correlation was assumed 0 for the crossover study (Hopkins 2021)
No data were available from the unpublished ulotaront studies (i.e., NCT04072354, NCT04092686).
No data available from RCT.
Correlation was assumed 0 for the crossover studies (Hopkins 2021, Tsukada 2023)
No data were available from the unpublished ulotaront studies (i.e., NCT04072354, NCT04092686).
No data available from RCT.
This outcome was considered rare event, and it was analyzed with a fixed-effects MH method. A correlation of 0 was assumed for crossover studies.
This outcome was considered rare event, and it was analyzed with a fixed-effects MH method. No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686).
No data available from RCT.
This outcome was considered rare event, and it was analyzed with a fixed-effects MH method. A correlation of 0 was used for crossover studies.
This outcome was considered rare event, and it was analyzed with a fixed-effects MH method.
No data available from RCT.
A correlation of 0 was assumed for crossover studies.
No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686).
No data available from RCT.
Terms that were considered as reported in the trials: dry mouth (no other relevant anticholinergic side-effects were reported such as urinary retention, constipation, mydriasis or blurred vision)
Only data from one study on healthy volunteers were available (Perini 2023)
No data available from RCT.
No data available from RCT.
Terms that were considered as reported in the trials: hypotension or orthostatic hypotension
No data available from RCT.
No data were available from the four trials on acute schizophrenia.
No data available from RCT.
A correlation of 0 was assumed for crossover studies.
No data were available from the four trials on acute schizophrenia.
No data available from RCT.
Terms that were considered as reported in the trials: nausea, vomiting, emesis
A correlation of 0 was assumed for crossover studies.
No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686). The study NCT04512066 examined ralmitaront while the other trials ulotaront (which is also a 5-HT1A receptor partial agonist).
No data available from RCT.
Terms that were considered as reported in the trials: QTc prolongation above ≥450 msec or an increase of ≥60 msec (any threshold was eligible)
A correlation of 0 was assumed for the two crossover studies with reported QTc prolongation.
No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686). The study NCT04512066 examined ralmitaront while the other trials ulotaront (which is also a 5-HT1A receptor partial agonist).
No data available from RCT.
One crossover study reported data for this outcome (Tsukada 2023). The analysis was adjusted for crossover and was reported for several timepoints within a day. The AUC was calculated and the divided by 24 hours for presentation.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686) and the study on Parkinson disease psychosis (Isaacson 2023).
No data available from RCT.
No data available from RCT.
No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023), and the unpublisshed study on ralmitaront (NCT04512066)
No data available from RCT.
Only one data from cossover RCT with assumed correlation of 0 (Hopkins 2021)
No data available from RCT.
No data available from RCT.
No data available from RCT.
SD was imputed from Huhn et al 2021. No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023), and the unpublisshed study on ralmitaront (NCT04512066)
No data available from RCT.
Terms considered included: restlessness (when was used to describe akathisia)
No data available from RCT.
No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023), and the unpublisshed study on ralmitaront (NCT04512066)
No data available from RCT.
Terms considered included: any extrapyramidal symptom, no finding in the movement disorder scales, use of anticholinergic medications (when used to treat extrapyramidal symptosm)
No data available from RCT.
No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023), and the unpublisshed study on ralmitaront (NCT04512066)
No data available from RCT.
Data were available only from one RCT on healthy volunteers.
No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023).
No data available from RCT.
No data available from RCT.
No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023).
No data available from RCT.
Data were available only from one RCT on healthy volunteers.
No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023).
No data available from RCT.
Terms that were considered as reported in the trials: fatigue, sedation, somnolence
Data were available only from two RCT on healthy volunteers. Correlation was assumed 0 for the crossover study (Hopkins 2021)
No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023).
No data available from RCT.
No data available from RCT.
No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023).
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
Terms that were considered as reported in the trials: dry mouth (no other relevant anticholinergic side-effects were reported such as urinary retention, constipation, mydriasis or blurred vision)
No data available from RCT.
No data available from RCT.
Terms that were considered as reported in the trials: hypotension or orthostatic hypotension
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
Terms that were considered as reported in the trials: nausea, vomiting, emesis
It should be noted that the study NCT04512066 examined ralmitaront (which compared to ulotaront is not a partial agonist of the 5-HT1A receptor)
No data available from RCT.
Terms that were considered as reported in the trials: QTc prolongation above ≥450 msec or an increase of ≥60 msec (any threshold was eligible)
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
Terms considered included: any weight increase, weight increase >7%
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
Terms that were considered as reported in the trials: fatigue, sedation, somnolence
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
No data available from RCT.
We did not conduct subgroup analyses and meta-regressions for the primary outcome due to the small number of included studies (i.e., 5) that precluded the exploration of potential reasons of heterogeneity.
We wanted to further explore the potential dose-effects of ulotaront or ralmitaront on improving overall symptoms in acute patients with schizophrenia, given that their doses were pooled in the analyses mentioned above. For this reason, we caclulated the effect sizes of each of the doses of these drugs compared to placebo (correcting the smaple of placebo as a shared control in a trial), and we plotted them in the figure below. No clear dose-effects can be observed.
*It should be noted that Koblan 2020 was a two-arm flexible dose study, and its effect size is placed in the middle of the range of the administered dose (50mg/d to 75mg/d), yet the median or mean dose in the trial could be different and was not reported. **The study of Isaacson 2023 was not presented here, as it was included participants with Parkinson disease psychosis.
We further conducted a dose response meta-analysis by plotting the
assumed response to the TAAR1 receptor that each of the ulotaront and
ralmitaront doses would elicity using the E50, Emax and the relationship
between dose and concentation in Michaelis-Menten formulas.
We did not conduct the following pre-planned sensitivity analyses for the primary outcome due to the small number of included studies (i.e., 5), i.e., 1) restricting the analysis to studies with an overall low risk of bias (no study had an overall low risk of bias) and 2) excluding estimates with imputed values (the N and SD of the ulotaront unpublished studies was imputed.
We evaluated the potential reporting bias for the primary outcome (overall symptoms in acute psychosis) using the ROB-ME tool.
| Name | Diagnosis | Sample size | Data availability |
|---|---|---|---|
| Isaacson (2023) | Parksinon disease psychosis | 39 | ✓ |
| Koblan (2020) | Schizophrenia spectrum | 245 | ✓ |
| NCT04072354 (2019) | Schizophrenia spectrum | 463 | ✓ (adult) / ?(adolescent) |
| NCT04092686 (2019) | Schizophrenia spectrum | 462 | ✓ |
| NCT04512066 (2020) | Schizophrenia spectrum | 287 | ✓ |
| NCT04825860 (2021) | Schizophrenia spectrum | 480 | ~ |
✓: A study result is available for inclusion in the meta-analysis.; ~:No study result is available for inclusion in the meta-analysis, for a reason unrelated to the P value, magnitude or direction of the result.; ?: Unclear whether an eligible study result was generated. *NCT04072354 included two parts, i.e., adults (sample size 435) and adolescents (sample size unclear but probably 28; planned 90). It should be noted that all of the other studies included adult populations. **NCT04825860 is an ongoing trial.
There were no sufficient data (i.e., 5 studies < 10) to examine small-study effects with funnel plots.
We conducted a comprehensive search of published and unpublished studies. Although we have not contacted the pharmaceutical companies (Hoffman-Roche for ralmitaront, and Sunovion/Sumitomo for ulotaront), it is not expected that any study was not identified in the search, as all of the trials were very recently published, and they should all have been registered.
There were no missing results in the studies identified (except for one small trial in adolescnets which data should not have an impact on the findings).There wre also no circumstances indicating potential for missing studies, and no clear patter of the results indicate potential missing studies (although funnel plots could not have been conducted due to the small number of studies). The same evaluation is relevant for both the comparisons of TAAR1 agonists vs. placebo and TAAR1 agonsits vs. antipsychotics. Therefore, there was assigned a low risk of bias in reporting bias.
The primary outcome was efficacy in reducing overall symptoms in acutely ill patients with psychosis, i.e., available data for adults with Parkinson disease psychosis and schizophrenia spectrum (analyzed separately). There were available data for two comparisons, i.e., TAAR1 agonists (ulotaront or ralmitaront) vs. placebo, and TAAR1 agonist (ralmitaront) vs. antipsychotics (risperidone). The summary of the evidence on the primary outcome for the above mentioned populations and comparisons are reported below.
| Source of evidence | Summary of the association | Bias due to study limitations | Bias due to reporting bias | Bias due to indirectedness | Bias due to other reasons |
| TAAR1 agonist. vs placebo in adults with Parkinson disease psychosis | n=1, k=37, SMD= -0.28, 95%CI: -0.95, 0.38 | 100% of the studies had an overall high risk of bias (due to missing outcome data, unclear direction and impact on the findings) | Low risk of reporting bias | Data available only for ulotaront. No other clear indication of indirectness in terms of population, interventions and outcomes | No clear indication of other biases |
| TAAR1 agonist. vs placebo in adults with schizophrenia spectrum disorder | n=4, k=1291, SMD=0.15, 95%CI: -0.05, 0.34, tau2=0.024 | All studies had an overall low risk of bias (some concerns due to missing outcome data, unclear direction and impact on the findings - potentially minimal) | Low risk of reporting bias | Data available only for ulotaront (3 studies) and ralmitaront (1 study).No other clear indication of indirectness in terms of population, interventions and outcomes | The phase III ulotaront trials conducted during COVID-19, which could be associated with factors assocaited with increased placebo effects and smaller effect sizes. No clear dose-effects. |
| TAAR1 agonist. vs other antipsychotics in adults with schizophrenia spectrum disorder | n=1, k=156, SMD=-0.53, 95%CI: -0.86, -0.20 | One study with an overall low risk of bias (some concerns due to missing outcome data, unclear direction and impact on the findings - potentially minimal) | Low risk of reporting bias | Data available only for ralmitaront (no data for ulotaront) and risperidone (no data for other antipsychotics). No other clear indication of indirectness in terms of population and outcomes | No clear indication of other biases |
k: number of studies, n: number of participants, I2: I-squared, SMD>0 indicates a favourable effect for the TAAR1 agonist. It should be noted that there is low confidence evidence that studies with high risk of bias in misisng outocme data may underestimate the effects (PMID: 37939743).
TAAR1 agonists may have little to no effect compared to placebo on overall symptoms in acutely ill adults with schizophrenia spectrum disorder (SMD=0.15, 95%CI: -0.05, 0.34). Specifically, the confidence in the evidence was low due to some concerns in imprecision (95%CI crossed line of no differences and 0.1) and some concerns in heterogeneity (although could not be well estimated due to the small number of studies).
TAAR1 agonists may be less efficacious with a medium effect size compared to other antipsychotics in improving overall symptoms in acutely ill adults with schizophrenia spectrum disorder (SMD=-0.53, 95%CI: -0.86, -0.20). The confidence in the evidence was low due to some concerns in imprecision (although 95%CI did not cross the range of equivalence, the sample size was small <800 participants) and some concerns in indirectness (no data ulotaront and other antipsychotics).
TAAR1 agonists may have little to no effect compared to placebo on overall symptoms in acutely ill adults with Parkinson disease psychosis (SMD=-0.28, 95%CI: -0.95, 0.38) and the evidence is very uncertain. Specifically, the confidence in the evidence was very low due to major concerns in imprecision (95%CI crossed beyond SMD -0.1 and 0.1, and the sample size was very small <800 participants), and some concerns in the risk of bias (study with a high risk of bias).
| text_description | outcome_new | duration | association | study_limitations | reporting_bias | indirectness | other_bias | |
|---|---|---|---|---|---|---|---|---|
| 2 | TAAR1 agonists vs. placebo in adults with schizophrenia | Overall symptoms (PANSS total) | 4-6 weeks | N=4 n=1291; SMD=0.15, 95%CI: -0.05, 0.34; tau2=0.0247 | All studies had overall low risk of bias | All eligible studies had usable data | No clear indication of indirectness | Two phase III trials conducted during COVID-19, which could be associated with factors assocaited with increased placebo effects and smaller effect sizes |
| 1 | TAAR1 agonists vs. placebo in Parkinson Disease Psychosis | Overall symptoms (NPI) | 6 weeks | N=1 n=37; SMD=-0.28, 95%CI: -0.95, 0.38 | 1 study with overall high risk of bias | 1 eligible study with usable data | No clear indication of indirectness | No clear indication of other biases |
| 27 | TAAR1 agonists vs. placebo in adults with schizophrenia | Response to treatment (≥50% or ≥20% reduction in PANSS total) | 4-6 weeks | N=4 n=1357; 23.7% vs. 18.7%, OR=1.35, 95%CI: 0.86, 2.12; tau2=0.1085 | All studies had overall low risk of bias | All eligible studies had usable data | No clear indication of indirectness | Two phase III trials conducted during COVID-19, which could be associated with factors assocaited with increased placebo effects and smaller effect sizes |
| 26 | TAAR1 agonists vs. placebo in Parkinson Disease Psychosis | Response to treatment (≥50% in SAPS-PD) | 6 weeks | N=1 n=39; 24% vs. 21.4%, OR=1.16, 95%CI: 0.24, 5.58 | 1 study with an overall low risk of bias | 1 eligible study with usable data | No clear indication of indirectness | No clear indication of other biases |
| 5 | TAAR1 agonists vs. placebo in adults with schizophrenia | Positive symptoms (PANSS positive subscale/factor) | 4 weeks | N=2 n=399; SMD=0.23, 95%CI: 0.03, 0.43; tau2=0 | All studies had overall low risk of bias | 50% of eligible studies and 28.9% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 4 | TAAR1 agonists vs. placebo in Parkinson Disease Psychosis | Positive symptoms (SAPS-PD) | 6 weeks | N=1 n=38; SMD=0.14, 95%CI: -0.52, 0.8 | 1 study with overall high risk of bias | 1 eligible study with usable data | No clear indication of indirectness | No clear indication of other biases |
| 7 | TAAR1 agonists vs. placebo in adults with schizophrenia | Negative symptoms (PANSS negative subscale/factor) | 4 weeks | N=2 n=399; SMD=0.23, 95%CI: -0.01, 0.48; tau2=0.0102 | All studies had overall low risk of bias | 50% of eligible studies and 28.9% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 10 | TAAR1 agonists vs. placebo in adults with schizophrenia | Depressive symptoms (PANSS anxiety/depression factor) | 4 weeks | N=2 n=399; SMD=0.17, 95%CI: -0.06, 0.39; tau2=0.0042 | All studies had overall low risk of bias | 50% of eligible studies and 28.9% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 9 | TAAR1 agonists vs. placebo in Parkinson Disease Psychosis | Cognitive impairment (MMSE) | 6 weeks | N=1 n=37; SMD=-0.51, 95%CI: -1.18, 0.17 | 1 study with overall high risk of bias | 1 eligible study with usable data | No clear indication of indirectness | No clear indication of other biases |
| 14 | TAAR1 agonists vs. placebo in any eligible population | Dropouts due to any reason | 4-6 weeks | N=5 n=1396; 22.9% vs. 19.6%, OR=1.22, 95%CI: 0.93, 1.6; tau2=0 | All studies had overall low risk of bias | 83.3% of eligible studies and 90.1% of participants had usable data | 80% studies and 97.2% participants with schizophrenia | No clear indication of other biases |
| 16 | TAAR1 agonists vs. placebo in any eligible population | Dropouts due to any reason | 1 day | N=2 n=93; 11.7% vs. 4.7%, OR=2.67, 95%CI: 0.48, 14.8 | All studies had overall low risk of bias | 16.7% of eligible studies and 14.9% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 18 | TAAR1 agonists vs. placebo in any eligible population | Dropouts due to adverse events | 4-6 weeks | N=3 n=497; 8.1% vs. 7.1%, OR=1.15, 95%CI: 0.58, 2.29; tau2=0 | All studies had overall low risk of bias | 50% of eligible studies and 32.1% of participants had usable data | 66.7% studies and 92.2% participants with schizophrenia | No clear indication of other biases |
| 20 | TAAR1 agonists vs. placebo in any eligible population | Dropouts due to adverse events | 1 day | N=3 n=161; 0.5% vs. 1.6%, OR=0.33, 95%CI: 0.02, 5.72 | 66.7% had overall low risk of bias | 25% of eligible studies and 25.7% of participants had usable data | 33.3% studies and 42.2% participants with schizophrenia | No clear indication of other biases |
| 22 | TAAR1 agonists vs. placebo in any eligible population | Any adverse event | 4-6 weeks | N=3 n=497; 48.7% vs. 54.6%, OR=0.79, 95%CI: 0.54, 1.15; tau2=0 | All studies had overall low risk of bias | 50% of eligible studies and 32.1% of participants had usable data | 66.7% studies and 92.2% participants with schizophrenia | No clear indication of other biases |
| 24 | TAAR1 agonists vs. placebo in any eligible population | Any adverse event | 1 day to 2 weeks | N=4 n=177; 52.3% vs. 11.4%, OR=8.49, 95%CI: 1.73, 41.66; tau2=1.7741 | 75% had overall low risk of bias | 33.3% of eligible studies and 28.3% of participants had usable data | 25% studies and 38.4% participants with schizophrenia | No clear indication of other biases |
| 65 | TAAR1 agonists vs. placebo in any eligible population | Serious adverse events | 4-6 weeks | N=3 n=497; 2.8% vs. 2.7%, OR=1.01, 95%CI: 0.32, 3.21; tau2=0 | All studies had overall low risk of bias | 50% of eligible studies and 32.1% of participants had usable data | 66.7% studies and 92.2% participants with schizophrenia | No clear indication of other biases |
| 67 | TAAR1 agonists vs. placebo in any eligible population | Serious adverse events | 1 day to 2 weeks | N=4 n=177; 4.6% vs. 1.6%, OR=3.02, 95%CI: 0.36, 25.76; tau2=0 | 75% had overall low risk of bias | 33.3% of eligible studies and 28.3% of participants had usable data | 25% studies and 38.4% participants with schizophrenia | No clear indication of other biases |
| 61 | TAAR1 agonists vs. placebo in any eligible population | Mortality due to any cause | 4-6 weeks | N=3 n=497; 3% vs. 1%, OR=3.15, 95%CI: 0.13, 78.11 | All studies had overall low risk of bias | 50% of eligible studies and 32.1% of participants had usable data | 66.7% studies and 92.2% participants with schizophrenia | No clear indication of other biases |
| 63 | TAAR1 agonists vs. placebo in any eligible population | Mortality due to any cause | 1 day to 2 weeks | N=4 n=177; not estimable effect size 0 events in both arms | All studies had overall low risk of bias | 33.3% of eligible studies and 28.3% of participants had usable data | 25% studies and 38.4% participants with schizophrenia | No clear indication of other biases |
| 45 | TAAR1 agonists vs. placebo in any eligible population | Nausea/vomitting | 4-6 weeks | N=3 n=497; 3.9% vs. 4.4%, OR=0.88, 95%CI: 0.25, 3.15; tau2=0.4981 | All studies had overall low risk of bias | 50% of eligible studies and 32.1% of participants had usable data | 66.7% studies and 92.2% participants with schizophrenia | No clear indication of other biases |
| 47 | TAAR1 agonists vs. placebo in any eligible population | Nausea/vomitting | 1 day | N=3 n=161; 19.5% vs. 1.6%, OR=15.14, 95%CI: 3.71, 61.75; tau2=0 | 66.7% had overall low risk of bias | 25% of eligible studies and 25.7% of participants had usable data | 33.3% studies and 42.2% participants with schizophrenia | No clear indication of other biases |
| 12 | TAAR1 agonists vs. placebo in any eligible population | Weight (kg) | 4 weeks | N=1 n=245; MD=0.4, 95%CI: -0.13, 0.93 | 1 study with an overall low risk of bias | 16.7% of eligible studies and 15.8% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 59 | TAAR1 agonists vs. placebo in any eligible population | Weight increased (≥7% increase or any cutoff) | 4 weeks | N=2 n=458; 1.1% vs. 1%, OR=1.04, 95%CI: 0.17, 6.47; tau2=0 | All studies had overall low risk of bias | 33.3% of eligible studies and 29.5% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 13 | TAAR1 agonists vs. placebo in any eligible population | Prolactin levels (ng/ml) | 4 weeks | N=1 n=227; MD=-0.58, 95%CI: -7.87, 6.7 | 1 study with an overall low risk of bias | 16.7% of eligible studies and 14.6% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 52 | TAAR1 agonists vs. placebo in any eligible population | Prolactin elevation (any cutoff) | 1 day | N=1 n=24; not estimable effect size 0 events in both arms | 1 study with an overall low risk of bias | 8.3% of eligible studies and 3.8% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 58 | TAAR1 agonists vs. placebo in any eligible population | Extrapyramidal symptoms | 4 weeks | N=1 n=245; 3.3% vs. 3.2%, OR=1.04, 95%CI: 0.25, 4.27 | 1 study with an overall low risk of bias | 16.7% of eligible studies and 15.8% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 57 | TAAR1 agonists vs. placebo in any eligible population | Akathisia | 4 weeks | N=1 n=245; 1.2% vs. 0.4%, OR=3.15, 95%CI: 0.13, 78.11 | 1 study with an overall low risk of bias | 16.7% of eligible studies and 15.8% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 35 | TAAR1 agonists vs. placebo in any eligible population | Agitation | 4 weeks | N=2 n=458; 5.5% vs. 4.2%, OR=1.35, 95%CI: 0.53, 3.43; tau2=0 | All studies had overall low risk of bias | 33.3% of eligible studies and 29.5% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 31 | TAAR1 agonists vs. placebo in any eligible population | Anxiety | 4 weeks | N=2 n=458; 2.6% vs. 7.6%, OR=0.32, 95%CI: 0.12, 0.85; tau2=0 | All studies had overall low risk of bias | 33.3% of eligible studies and 29.5% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 33 | TAAR1 agonists vs. placebo in any eligible population | Anxiety | 1 day | N=1 n=69; not estimable effect size 0 events in both arms | 1 study with an overall low risk of bias | 8.3% of eligible studies and 11% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 49 | TAAR1 agonists vs. placebo in any eligible population | Sedation | 4-6 weeks | N=2 n=284; 8.1% vs. 7.2%, OR=1.14, 95%CI: 0.44, 3; tau2=0 | All studies had overall low risk of bias | 33.3% of eligible studies and 18.3% of participants had usable data | 50% studies and 86.3% participants with schizophrenia | No clear indication of other biases |
| 50 | TAAR1 agonists vs. placebo in any eligible population | Sedation | 1 day | N=2 n=93; 40.6% vs. 8.3%, OR=7.54, 95%CI: 2.56, 22.22; tau2=0 | All studies had overall low risk of bias | 16.7% of eligible studies and 14.9% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 55 | TAAR1 agonists vs. placebo in any eligible population | Insomnia | 4 weeks | N=2 n=458; 4.7% vs. 4.8%, OR=0.98, 95%CI: 0.07, 13.43; tau2=2.8647 | All studies had overall low risk of bias | 33.3% of eligible studies and 29.5% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 37 | TAAR1 agonists vs. placebo in any eligible population | Headache | 4 weeks | N=2 n=458; 7.9% vs. 9%, OR=0.86, 95%CI: 0.43, 1.69; tau2=0 | All studies had overall low risk of bias | 33.3% of eligible studies and 29.5% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 39 | TAAR1 agonists vs. placebo in any eligible population | Headache | 1 day | N=1 n=69; 11.5% vs. 20.6%, OR=0.5, 95%CI: 0.13, 1.89 | 1 study with an overall low risk of bias | 8.3% of eligible studies and 11% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 69 | TAAR1 agonists vs. placebo in any eligible population | QTc interval (msec) | 1 day | N=1 n=62; MD=1.25, 95%CI: -2.87, 5.37 | 1 study with overall some concerns in risk of bias | 8.3% of eligible studies and 9.9% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 53 | TAAR1 agonists vs. placebo in any eligible population | QTc prolongation (any cutoff) | 4 weeks | N=1 n=245; not estimable effect size 0 events in both arms | 1 study with an overall low risk of bias | 16.7% of eligible studies and 15.8% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 54 | TAAR1 agonists vs. placebo in any eligible population | QTc prolongation (any cutoff) | 1 day | N=2 n=92; 8.1% vs. 1.6%, OR=5.32, 95%CI: 0.6, 46.78 | 50% had overall low risk of bias | 16.7% of eligible studies and 14.7% of participants had usable data | 50% studies and 73.9% participants with schizophrenia | No clear indication of other biases |
| 41 | TAAR1 agonists vs. placebo in any eligible population | Hypotension | 6 weeks | N=1 n=39; 52.4% vs. 78.6%, OR=0.3, 95%CI: 0.07, 1.32 | 1 study with an overall low risk of bias | 16.7% of eligible studies and 2.5% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 42 | TAAR1 agonists vs. placebo in any eligible population | Dizziness | 6 weeks | N=1 n=39; 16% vs. 7.1%, OR=2.48, 95%CI: 0.25, 24.65 | 1 study with an overall low risk of bias | 16.7% of eligible studies and 2.5% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 43 | TAAR1 agonists vs. placebo in any eligible population | Dizziness | 1 day | N=2 n=137; 19.9% vs. 3.5%, OR=6.89, 95%CI: 1.98, 23.92; tau2=0 | 50% had overall low risk of bias | 16.7% of eligible studies and 21.9% of participants had usable data | 50% studies and 49.6% participants with schizophrenia | No clear indication of other biases |
| 29 | TAAR1 agonists vs. placebo in any eligible population | Anticholinergic symptom | 1 day | N=1 n=69; 15.3% vs. 1.4%, OR=12.44, 95%CI: 0.66, 234.38 | 1 study with an overall low risk of bias | 8.3% of eligible studies and 11% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 3 | TAAR1 agonists vs. antipsychotics in adults with schizophrenia | Overall symptoms (PANSS total) | 4 weeks | N=1 n=156; SMD=-0.53, 95%CI: -0.86, -0.2 | 1 study with an overall low risk of bias | 1 eligible study with usable data | No clear indication of indirectness | No clear indication of other biases |
| 28 | TAAR1 agonists vs. antipsychotics in adults with schizophrenia | Response to treatment (≥50% or ≥20% reduction in PANSS total) | 4 weeks | N=1 n=214; 7.9% vs. 13.5%, OR=0.55, 95%CI: 0.22, 1.35 | 1 study with an overall low risk of bias | 1 eligible study with usable data | No clear indication of indirectness | No clear indication of other biases |
| 6 | TAAR1 agonists vs. antipsychotics in adults with schizophrenia | Positive symptoms (PANSS positive subscale/factor) | 4 weeks | N=1 n=156; SMD=-0.55, 95%CI: -0.89, -0.22 | 1 study with an overall low risk of bias | 1 eligible study with usable data | No clear indication of indirectness | No clear indication of other biases |
| 8 | TAAR1 agonists vs. antipsychotics in adults with schizophrenia | Negative symptoms (PANSS negative subscale/factor) | 4 weeks | N=1 n=156; SMD=-0.13, 95%CI: -0.46, 0.19 | 1 study with an overall low risk of bias | 1 eligible study with usable data | No clear indication of indirectness | No clear indication of other biases |
| 11 | TAAR1 agonists vs. antipsychotics in adults with schizophrenia | Depressive symptoms (PANSS anxiety/depression factor) | 4 weeks | N=1 n=156; SMD=-0.23, 95%CI: -0.56, 0.1 | 1 study with an overall low risk of bias | 1 eligible study with usable data | No clear indication of indirectness | No clear indication of other biases |
| 15 | TAAR1 agonists vs. antipsychotics in any eligible population | Dropouts due to any reason | 4 weeks | N=1 n=214; 22.9% vs. 18.9%, OR=1.27, 95%CI: 0.63, 2.56 | 1 study with an overall low risk of bias | 16.7% of eligible studies and 13.8% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 17 | TAAR1 agonists vs. antipsychotics in any eligible population | Dropouts due to any reason | 1 day | N=1 n=71; 14.3% vs. 5.6%, OR=2.83, 95%CI: 0.51, 15.69 | 1 study with an overall low risk of bias | 50% of eligible studies and 71% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 19 | TAAR1 agonists vs. antipsychotics in any eligible population | Dropouts due to adverse events | 4 weeks | N=1 n=214; 6.4% vs. 1.4%, OR=5.02, 95%CI: 0.62, 40.38 | 1 study with an overall low risk of bias | 16.7% of eligible studies and 13.8% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 21 | TAAR1 agonists vs. antipsychotics in any eligible population | Dropouts due to adverse events | 1 day | N=1 n=71; not estimable effect size 0 events in both arms | 1 study with an overall low risk of bias | 50% of eligible studies and 71% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 23 | TAAR1 agonists vs. antipsychotics in any eligible population | Any adverse event | 4 weeks | N=1 n=214; 26.5% vs. 48.6%, OR=0.38, 95%CI: 0.21, 0.68 | 1 study with an overall low risk of bias | 16.7% of eligible studies and 13.8% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 25 | TAAR1 agonists vs. antipsychotics in any eligible population | Any adverse event | 1 day | N=1 n=71; 97.1% vs. 41.7%, OR=47.6, 95%CI: 5.85, 387.2 | 1 study with an overall low risk of bias | 50% of eligible studies and 71% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 66 | TAAR1 agonists vs. antipsychotics in any eligible population | Serious adverse events | 4 weeks | N=1 n=214; 2.5% vs. 0.7%, OR=3.79, 95%CI: 0.19, 74.42 | 1 study with an overall low risk of bias | 16.7% of eligible studies and 13.8% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 68 | TAAR1 agonists vs. antipsychotics in any eligible population | Serious adverse events | 1 day | N=1 n=71; 4.2% vs. 1.4%, OR=3.17, 95%CI: 0.13, 80.58 | 1 study with an overall low risk of bias | 50% of eligible studies and 71% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 62 | TAAR1 agonists vs. antipsychotics in any eligible population | Mortality due to any cause | 4 weeks | N=1 n=214; not estimable effect size 0 events in both arms | 1 study with an overall low risk of bias | 16.7% of eligible studies and 13.8% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 64 | TAAR1 agonists vs. antipsychotics in any eligible population | Mortality due to any cause | 1 day | N=1 n=71; not estimable effect size 0 events in both arms | 1 study with an overall low risk of bias | 50% of eligible studies and 71% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 46 | TAAR1 agonists vs. antipsychotics in any eligible population | Nausea/vomitting | 4 weeks | N=1 n=214; 1.4% vs. 8.1%, OR=0.16, 95%CI: 0.03, 0.84 | 1 study with an overall low risk of bias | 16.7% of eligible studies and 13.8% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 48 | TAAR1 agonists vs. antipsychotics in any eligible population | Nausea/vomitting | 1 day | N=1 n=71; 34.7% vs. 1.4%, OR=38.83, 95%CI: 2.19, 687.51 | 1 study with an overall low risk of bias | 50% of eligible studies and 71% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 60 | TAAR1 agonists vs. antipsychotics in any eligible population | Weight increased (≥7% increase or any cutoff) | 4 weeks | N=1 n=214; 1.4% vs. 10.8%, OR=0.12, 95%CI: 0.02, 0.58 | 1 study with an overall low risk of bias | 16.7% of eligible studies and 13.8% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 36 | TAAR1 agonists vs. antipsychotics in any eligible population | Agitation | 4 weeks | N=1 n=214; 6% vs. 0.7%, OR=9.56, 95%CI: 0.54, 167.96 | 1 study with an overall low risk of bias | 16.7% of eligible studies and 13.8% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 32 | TAAR1 agonists vs. antipsychotics in any eligible population | Anxiety | 4 weeks | N=1 n=214; 3.6% vs. 6.8%, OR=0.51, 95%CI: 0.14, 1.83 | 1 study with an overall low risk of bias | 16.7% of eligible studies and 13.8% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 34 | TAAR1 agonists vs. antipsychotics in any eligible population | Anxiety | 1 day | N=1 n=71; 1.2% vs. 8.3%, OR=0.13, 95%CI: 0.01, 2.71 | 1 study with an overall low risk of bias | 50% of eligible studies and 71% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 51 | TAAR1 agonists vs. antipsychotics in any eligible population | Sedation | 1 day | N=1 n=71; 60% vs. 13.9%, OR=9.3, 95%CI: 2.91, 29.72 | 1 study with an overall low risk of bias | 50% of eligible studies and 71% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 56 | TAAR1 agonists vs. antipsychotics in any eligible population | Insomnia | 4 weeks | N=1 n=214; 5.7% vs. 6.8%, OR=0.84, 95%CI: 0.26, 2.65 | 1 study with an overall low risk of bias | 16.7% of eligible studies and 13.8% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 38 | TAAR1 agonists vs. antipsychotics in any eligible population | Headache | 4 weeks | N=1 n=214; 6.4% vs. 8.1%, OR=0.78, 95%CI: 0.27, 2.28 | 1 study with an overall low risk of bias | 16.7% of eligible studies and 13.8% of participants had usable data | No clear indication of indirectness | No clear indication of other biases |
| 40 | TAAR1 agonists vs. antipsychotics in any eligible population | Headache | 1 day | N=1 n=71; 11.4% vs. 2.8%, OR=4.52, 95%CI: 0.48, 42.59 | 1 study with an overall low risk of bias | 50% of eligible studies and 71% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 44 | TAAR1 agonists vs. antipsychotics in any eligible population | Dizziness | 1 day | N=1 n=71; 28.6% vs. 2.8%, OR=14, 95%CI: 1.68, 116.49 | 1 study with an overall low risk of bias | 50% of eligible studies and 71% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |
| 30 | TAAR1 agonists vs. antipsychotics in any eligible population | Anticholinergic symptom | 1 day | N=1 n=71; 15.3% vs. 1.4%, OR=13.16, 95%CI: 0.7, 247.71 | 1 study with an overall low risk of bias | 50% of eligible studies and 71% of participants had usable data | 0% studies and 0% participants with schizophrenia | No clear indication of other biases |